MicroRNAs (miRNAs) are 21-22 nucleotide non-coding RNAs that are sometimes expressed in a lineage-specific fashion and thus have the potential to control cell fate decisions (Ambros, 2001; Bartel, 2004; Johnston, 2003). There are over 300 known miRNAs and each is thought to target numerous mRNA transcripts for either degradation or, more often, translational inhibition. miRNAs typically bind to 3′ untranslated regions (UTRs) of mRNAs through inexact sequence matching. The lack of precise sequence homology between miRNA and targets has made target prediction difficult, although it does appear that sequence matching of the 5′ end of the miRNA and a permissive secondary structure of target mRNA are important features (Lewis, 2003; Zhao, 2005). Despite recent advances in target prediction, only a handful of miRNA targets have been validated thus far resulting in limited knowledge of biological roles for most miRNAs.
miRNAs may play a role in regulation of stem cell fates (Hatfield, 2005; Forstemann, 2005; Cheng, 2005), but direct experimental evidence and a mechanistic understanding of miRNA regulation of cell lineages have been lacking. In Drosophila, the dorsal vessel, a primitive heart, is composed of distinct cell types, each arising from progenitor cells that follow stereotypic lineage decisions, providing a tractable system in which to study the possible involvement of miRNAs in cell fate decisions. We previously demonstrated that miR-1-1 and miR-1-2 are redundant muscle-specific mammalian miRNAs that play a role in cardiogenesis (Zhao, 2005). Mouse miR-1-1 and miR-1-2 were regulated by serum response factor (SRF), a central transcriptional regulator of muscle differentiation, and excess miR-1 in vivo resulted in premature withdrawal of cardiomyocytes from the cell cycle. We have found that miR-1 targets the Notch ligand Delta, and that when introduced into cells, inhibits Delta protein expression.